Cardiovascular diseases (CVD) are the number one cause of death and are projected to remain the leading cause of death. Among CVD, worldwide prevalence estimates for hypertension, or high blood pressure (BP), may be as much as 1 billion individuals. Hypertension is the single biggest risk factor for stroke and heart attacks, ad a primary or contributing cause of death for 348,000 Americans in 2008, or nearly 1,000 deaths a day. With prevalence higher than 33% in United States, hypertension remains an increasingly important medical and public health issue. Evidence has shown the importance of the brain renin-angiotensin system (RAS) in the maintenance of normal BP and in the neuro-cardiovascular dysregulation leading to hypertension. Angiotensin (Ang)-II, by means of its type 1 receptor (AT1R), promotes increased sympathetic activity, including enhanced glutamatergic activity, salt and water reabsorption, vasoconstriction, aldosterone and vasopressin release and inflammation, all contributing to high BP. ACE2 (angiotensin converting enzyme type 2) cleaves Ang- II into the vasodilator peptide angiotensin-(1-7) (Ang-(1-7)) and has been identified as a pivotal player in the ACE2/Ang-(1-7)/Mas receptor compensatory axis of the RAS. While numerous overexpression studies have established the benefits of ACE2 in preventing the progression and improving the treatment of hypertension in experimental models, our group our group was the first to show post- translational impairment of endogenous brain ACE2 in hypertension. ACE2 shedding, a process by which the ACE2 ectodomain is cleaved from the plasma membrane and secreted into the surrounding milieu, is one of these post-translational mechanisms. Our preliminary data suggest that ADAM17 (A Disintegrin And Metalloprotease) mediates ACE2 shedding, thus contributing to a loss in cell membrane enzyme activity during the development of hypertension. The central hypothesis of this proposal is that Ang-II promotes ACE2 shedding, leading to RAS over-activity and neurogenic hypertension. Targeting of ADAM17-mediated shedding will restore ACE2 compensatory properties and reduce hypertension. The immediate objectives of this application are: 1) to characterize the signaling pathways leading to ACE2 shedding; 2) to identify therapeutic approaches to preserve ACE2 compensatory activity in hypertension; and to 3) address the clinical relevance of secreted ACE2 (sACE2) in human hypertension. To test our hypothesis, we will use state-of-the-art in vitro and in vivo molecular, cellular, pharmacological and clinical approaches combined with novel and unique genetic models with selective deletion of ADAM17 in pre-sympathetic neurons and cardiovascular analysis in the DOCA-salt model of neurogenic hypertension.